Autophagy inhibition-mediated epithelial\u2013mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis

Catherine M Hill ,Mark G Jones,Andrew J Steele,Dian Liu,Ben G Marshall,Serena Chee ,Christopher J Brereton,David C Hancock ,Christian Ottensmeier ,Xin Lü ,Luca Richeldi,Liudi Yao,Donna E Davies,Juanjuan Li,Sophie Fletcher ,Aiman Alzetani,Yilu Zhou,Franco Conforti,Julian Downward,Yihua Wang

doi:10.1038/s41419-019-1820-x

Abstract

Idiopathic pulmonary fibrosis (IPF), the prototypic progressive fibrotic interstitial lung disease, is thought to be a consequence of repetitive micro-injuries to an ageing, susceptible alveolar epithelium. Ageing is a risk factor for IPF and incidence has been demonstrated to increase with age. Decreased (macro)autophagy with age has been reported extensively in a variety of systems and diseases, including IPF. However, it is undetermined whether the role of faulty autophagy is causal or coincidental in the context of IPF. Here, we report that in alveolar epithelial cells inhibition of autophagy promotes epithelial–mesenchymal transition (EMT), a process implicated in embryonic development, wound healing, cancer metastasis and fibrosis. We further demonstrate that this is attained, at least in part, by increased p62/SQSTM1 expression that promotes p65/RELA mediated-transactivation of an EMT transcription factor, Snail2 (SNAI2), which not only controls EMT but also regulates the production of locally acting profibrogenic mediators. Our data suggest that reduced autophagy induces EMT of alveolar epithelial cells and can contribute to fibrosis via aberrant epithelial–fibroblast crosstalk.

Highlights

Idiopathic pulmonary fibrosis (IPF) is the most common type of chronic, progressive fibrotic interstitial lung disease
We observed evidence of autophagy inhibition as determined by p62/SQSTM1 accumulation in lung epithelial cells in IPF samples (Fig. 1; Supplementary Fig. S1a). p62/ SQSTM1 is a key protein involved in autophagy that recognises cellular waste, which is sequestered and degraded by autophagy[15]
Given that p62/SQSTM1 protein levels are predominantly regulated by autophagic activity[17], these results suggest that autophagic activity is downregulated in IPF epithelial cells

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is the most common type of chronic, progressive fibrotic interstitial lung disease. It occurs with comparable incidence to that of stomach, brain and testicular cancer[1], and the median survival of patients with IPF is only 3 years[2,3]. IPF is characterised by aberrant extracellular matrix (ECM) deposition, which leads to decreased lung compliance, Evidence suggests that interacting genetic and environmental factors are crucial for the development of IPF, with repetitive injuries to aged alveolar epithelium thought to play an important role[2]. Ageing is a risk factor for IPF, with disease incidence increasing with age[3]. Decreased (macro)autophagy with age has been reported extensively in a variety of systems and diseases[4], including IPF5–9. Autophagy is a tightly controlled, evolutionarily conserved process for the lysosomal degradation of cytoplasmic cargo, long-lived proteins and organelles

Methods

Results

Conclusion